HEXAMETHONIUM-INDUCED AND METHYLLYCACONITINE-INDUCED CHANGES IN ACETYLCHOLINE-RELEASE FROM RAT MOTOR-NERVE TERMINALS

1 The neuronal nicotinic receptor antagonists hexamethonium and methyl lycaconitine (MLA) have been used to study the putative prejunctional nicotinic ACh receptors (AChRs); mediating a negative-feedback control of ACh release from motor nerve terminals in voltage-clamped rat phre nic nerve/hemidiaphragm preparations. 2 Hexamethonium (200 mu M), but not MLA (0.4-2.0 mu M), decreased the time constant of decay of both e ndplate currents (e.p.cs) and miniature endplate currents (m.e.p.cs), indicating endplate ion channel block with hexamethonium. However, dri ving function analysis and reconvolution of e.p.cs and m.e.p.cs indica ted that this ion channel block did not compromise the analysis of e.p .c. quantal content. 3 At low frequencies of stimulation (0.5-2 Hz), h examethonium (200 mu M) and MLA (2.0 mu M) increased e.p.c. quantal co ntent by 30-40%. At high frequencies (50-150 Hz) neither compound affe cted e.p.c. quantal content. All effects on quantal content were paral leled by changes in the size of the pool of quanta available for relea se. 4 The low frequency augmentation of e.p.c. quantal content by hexa methonium was absent when extracellular [Ca2+] was lowered from 2.0 to 0.5 mM. 5 At the concentrations studied, MLA and hexamethonium produc ed a small (10-20%) decrease in the peak amplitude of m.e.p.cs. 6 Neit her apamin (100 nM) nor charybdotoxin (80 nM) had effects on spontaneo us or nerve evoked current amplitudes at any frequency of stimulation. Thus the ability of nicotinic antagonists to augment e.p.c. quantal c ontent is not due to inhibition of Ca2+-activated (K+)-channels. 7 We suggest that hexamethonium and MLA increase evoked ACh release by bloc king prejunctional nicotinic AChRs. These receptors exert a negative f eedback control over evoked ACh release and are probably of the a-bung arotoxin-insensitive neuronal type.